Breakthrough FDA approval for first solid tumor cell therapy signals new era for cancer treatment 

Immunotherapies, including cellular immunotherapies, have dramatically impacted the treatment of cancer. Recent advances in the field, such as autologous (patient-derived) chimeric antigen receptor (CAR)-T cell therapies, have yielded remarkable results in relatively rare blood-based cancers. These results have driven an explosion in the research and development of different cellular products, including both autologous and allogeneic (“off-the-shelf”) versions of T cells, natural killer (NK) cells and macrophages. However, until recently, the prospect for using cellular therapies to treat solid tumors remained elusive.

This situation changed in February this year, when the FDA approved lifileucel (Amtagvi) for the treatment of melanoma. Lifileucel is an autologous tumor infiltrating lymphocyte (TIL) product — a particular type of T cells generated by taking T cells from patient tumors, expanding them in the laboratory and then re-infusing them back into the patient — similar in many regards to autologous CAR-T cell products. Clearly, in order to manufacture lifileucel, patients need suitable resectable tumors for recovery of sufficient quantity and quality of TILs. The quality factor is particularly problematic since the product is a mixture of multiple CD4+ and CD8+ T cell lineages but may also contain monocytes and other lymphocytes, including B cells and natural killer cells.ⁱⁱ It is not clear what proportion of the melanoma patient population will qualify for this therapy.

From the clinic to FDA approval

Lifileucel was approved on the basis of a clinical trial conducted by Iovance Biotherapeutics, in which 73 melanoma patients (whose disease had advanced despite immune checkpoint (PD-1/PD-L1) inhibitor therapy) were treated at the approved minimum dose level of 7.5 billion cells. Of these, 48 patients (31.5%) experienced a partial or complete response i.e., either a >30% decline in tumor size (partial response, PR) or disappearance of the tumor (complete response, CR). In about half the patients who responded, there was no evidence of disease recurrence or progression for over a year after treatment. The longest lasting response was reported as lasting almost 5 years at the European Society of Medical Oncology (ESMO) Immuno-oncology Congress in December 2023.ⁱ

TIL therapy originated from the laboratory of Dr. Steven Rosenberg at the National Cancer Institute (NCI), with the first clinical trial being undertaken (in advanced melanoma) by Dr. Rosenberg in the late 1980s.^iv Despite demonstrating that the treatment could lead to tumor regression, challenges with manufacturing a TIL product and limited understanding of the role of the immune system in controlling cancer hindered development of the technology. The success of today’s CAR-T cells and approval of lifileucel demonstrate the tremendous progress made in the field in the decades since the original TIL trials.

While the approval of one cell therapy product in one solid tumor indication does not ensure others will follow, the success of lifileucel represents a significant breakthrough in the potential of cell therapies for treating solid tumors, which represent approximately 90 percent of adult cancers. The developers of CAR-T, CAR-NK and other cell products can take heart in the result. And, hopefully, it will help re-kindle investor and partner interest in the field, who may now see renewed promise and opportunity in the field of immune cell therapies.

Balancing efficacy and affordability

However, despite this positive development, the cost of cell therapies remains a challenge. Approved autologous CAR-T cells cost in the range US$400,00-US$500,000. Lifileucel is no different. Iovance has advised that the cost of a single treatment will be US$515,000. While melanoma is not a common tumor type (in the US.., at least), it remains to be seen whether the healthcare system will be able to cope with such an expensive treatment. In addition, the complexity of cell collection and expansion means that these treatments cannot be made available “on demand” or outside of centralized, specialized treatment centres.

The effectiveness of the TIL therapy underscores the benefits of personalized cell therapy — matching the treatment to the individual disease. The mechanism by which lifileucel generates clinical responses is unknownⁱⁱ and teasing out the phenotype and specificity of the T cells in the product will require extensive translational research. This may ultimately provide the basis for designing allogeneic T cell therapies, enabling wider application of the therapy at a more reasonable cost.

In addition to cost issues, product safety will be a key driver for the uptake of cellular therapies. CAR-T therapies can cause serious and life-threatening complications, including cytokine release syndrome (CRS), neurotoxicity, and the development of secondary cancers. While AMTAGVI’s side effect profile is different, the clinical study that formed the basis for approval saw a 7.5% treatment-related fatality rate. Such serious side effects with T cell products may limit their potential, particularly for non-oncology indications (which are now being explored by cell therapy companies). This prompts the question of whether other immune cells, such as natural killer (NK) cells, might offer safer and better alternatives, bypassing the side effects observed with CAR-T and TIL therapies. Early clinical studies suggest that CAR-NK cells have a much better safety profile compared to CAR-T cells.^v

While lifileucel represents an important step forward for the field of solid tumor cell therapies, embracing allogeneic approaches with improved safety profiles will propel cell therapies toward their full potential.

Achieving this will require continued research, investment, and collaboration to overcome current challenges and unlock the widespread benefits of allogeneic cell therapies for solid tumors — promising simpler, safer and more cost-effective solutions that could revolutionize cancer treatment accessibility and efficacy.

Ian Nisbet, Ph.D., is the COO and Professor Alan Trounson, Ph.D., AO is the CEO of Cartherics, a biotechnology company developing immune cell therapies for the treatment of solid cancers.

References

1. U.S. Food and Drug Administration. FDA grants accelerated approval to lifileucel for unresectable or metastatic melanoma. Available from: https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-lifileucel-unresectable-or-metastatic-melanoma
2. Iovance Biotherapeutics, Inc. Prescribing information – Amtagvi (lifileucel) suspension for intravenous infusion. 2024.
3. Wermke M, Chesney J, Whitman E, et al. Long-term efficacy and patterns of response of lifileucel tumor-infiltrating lymphocyte (TIL) cell therapy in patients with advanced melanoma: a 4-year analysis of the C-144-01 study. Ann Oncol. 2023;34(suppl 2):100589. doi:10.1016/iotech/iotech100589
4. Topalian SL, Solomon D, Avis FP, Chang AE, Freerksen DL, Linehan WM, Lotze MT, Robertson CN, Seipp CA, Simon P, et al. Immunotherapy of patients with advanced cancer using tumor-infiltrating lymphocytes and recombinant interleukin-2: a pilot study. J Clin Oncol. 1988;6(5):839-853.
5. Marin D, Li Y, Basar R, et al. Safety, efficacy and determinants of response of allogeneic CD19-specific CAR-NK cells in CD19+ B cell tumors: a phase 1/2 trial. Nat Med. 2024;30(4):772-784. doi:10.1038/s41591-023-02785-8

---

Filed Under: Cell & gene therapy, Immunology, Oncology
Tagged With: Autologous cell therapy, CAR-T, cell therapy, immunotherapy, oncology, Solid tumor cell therapy, TIL therapy
 

---